Broadly, this study proposes to investigate the molecular etiology of iron overload that accompanies chronic hepatitis C (CMC) and alcoholic liver disease. Iron overload has been shown to significantly and negatively affect the progression of these diseases;therefore, understanding etiology is important in order to gain insight into diagnosis of risk stratification and therapeutic targets. Systemic iron metabolism is regulated by the peptide hormone hepcidin, which is expressed in the liver. It is likely that the iron overload in chronic liver disease represents dysregulation of systemic iron metabolism by suppression of hepcidin in response to liver injury. Candidates for the suppressor of hepcidin include hepatocyte growth factor (HGF) and growth and differentiation factor 15 (GDF15). The regulation of hepcidin by HGF and GDF15 will be explored in vitro in primary mouse hepatocytes and human hepatoma cell lines. The effects of HGF and GDF15 with respect to hepcidin expression and iron parameters (serum iron concentration, serum ferritin, and liver tissue iron deposition) will be examined in vivo in mouse models of liver-specific HGF and GDF15 overexpression. A non-inflammatory mouse model of hepatic injury (EtOH-induced) and an inflammatory mouse model of hepatic injury (Concanavalin A-induced) will be used to investigate the effects of liver injury and repair on hepcidin expression, HGF and GDF-15. Finally, a clinical correlate will compare the serum hepcidin, HGF and GDF-15 values to chronic hepatitis C patient liver iron content (available from patient liver biopsy) and patient serum iron, ferritin measurements. In the United States patients with chronic hepatitis C (CHC) represent the largest burden of chronic hepatic disease in the United States: CHC is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. It is increasingly evident that liver iron loading is a significant contributive factor in the progression of CHC. This study proposes to investigate the molecular causes of liver iron loading in CHC and other chronic liver disease. A minor weakness is that, to date, the candidate has not had an opportunity to attend national meeting or specialized workshops. Nor has she had an opportunity to present her research at a national meeting. Plans for these kinds of valuable experiences were not found in the application.